Urea and thiourea derivatives



Patented Dec. 14, 1943 UNITED STATE ff.

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OFFICE UREA AND THIOUREA DERIVATIVES Johannes S. Buck, Bronxville, andEdwin J. de Beer, Yonkers, N. Y., assignors to Burroughs Wellcome & 00.(U. S. A.) Inc., New York, N. Y., a corporation of New York No Drawing.Application July 18, 1941, Serial No. 402,940

4 Claims.

This invention relates to urea and thiourea derivatives and particularlyto products of the above type having sedative, hypnotic or anestheticproperties, generally herein referred to as hypnotics.

An object of the invention is to obtain novel urea and thioureaderivatives.

Another object is to provide a novel and improved hypnotic.

Another object is to provide a hypnotic having novel and improvedcharacteristics.

Other objects and advantages will be apparent as the nature of theinvention is more fully disclosed.

Although the novel features which are believed in which R represents analkyl radical having less than 8 carbon atoms, A represents V or S,

R and B" each represent hydrogen or alkyl radicals having less than 8carbon atoms and which may or may not be the same radical, and PIrepresents a haloaryl or haloaralkyl radical such as a halogenatedphenyl, benzyl or phenethyl radical which radical may be furthersubstituted by one or more alkyl, or alkoxy radicals of less than 8carbon atoms each. R and R together must contain at least 8 carbonatoms.

In the case of a phenyl radical the ring is directly bound to the N. Inthe case of the benzyl and phenethyl radicals the ring is aliphaticallybound to the N by -CH2 and CH2CH2 respectively. The term "halogenatedrefers to a radical substituted one or more times by a halogen.

The following specific examples of such ureas and thioureas are givenonly as illustrative of the general class embodied Within the aboveformula:

N-ethyl-N- (2-chlorophenyl) urea N- ethyl-N- (3-chloro -2 -methylphenyl)urea N-ethyl-N- (3-chloro-2-methylphenyl) thiourea N-n-butyl-N-(4-bromo-2-methylphenyl) urea N-methyl-N- (2-bromo-4-ethylphenyl) urea.N-ethyl-N- (4-bromo-2-ethylphenyl) urea N-ethyl-N-(4-bromo-2-ethylphenyl) thiourea N-ethyl-N- (3-bromo-6-ethoxyphenyl)urea N-n-propyl-N- (4-bromo-2-methylphenyl) urea N-ethyl-N-(4-chlo-r0-2-methylphenyl) thiourea N-inethyl-N-(2-broino-5-ethoxybenzyl) urea N-methyl-N- (3-bromo-4-methoxybenzyl)urea N-methyl-N- (3-chloro-4-ethoxybenzyl) thiourea N-methyl-N-(Z- bromo5 methoxyphenethyl) urea N-methyl-N- (3- chloro 4 methoxyphenethyl) ureaN-ethyl-N- (3-bromo-4-ethoxyphenethyl) urea N-methyl-N- (-bromophenyl)-N'-allylthiourea Specific examples of methods of making representativesubstances are as follows:

Example 1 N-n-propyl-N- (4 -bromo-2-methylphenyl) urea may be made asfollows The base liberated from 13.3 grams n-propyl-4-broino-2-methylaniline hydrochloride, is dissolved in cc. per centethyl alcohol and 5 grams nitrourea added. After warming on the Waterbath for one hour, the solution is further treated with 3 gramsnitrourea, and finally, with a further 2 grams nitrourea. After boilingoff the alcohol, water is added, the product extracted with ether, andthe extract dried with anhydrous potassium carbonate and the etherevaporated. The residue is dissolved in hexane. On long standing in arefrigerator, crystals are obtained. These are recrystallized fromhexane until pure.

The compound forms white or colorless needle prisms melting at about 95C.

Example 2 CHsCHzCHaCHrIIP-C O-NH:

N-n-butyl-N- (4-bromo- 2 methylphenyl) urea may be made as follows- 4bromo 2 methylaniline is converted, by means of n-butyltoluenesulfonate,into n-butyl- 4-bromo-2-methylaniline. This base is then converted intothe above urea by means of nitrourea. The compound could not becrystallized so, after partitioning, washing, and drying, it wasdistilled in a molecular still, the fraction boiling at about 105 C.-130C. (temperature of air bath) at 0.001 mm. pressure being collected.

Example 3 CHaCHrIIT-C O-NH2 Example 4 N-ethyl-N(3-chloro-2-methylphenyl) urea is prepared substantially as in Example3, from ethyl-3-chloro-2-methyl-aniline and nitrourea. The compoundforms large irregular prisms, melting at about 94 C. when recrystallizedfrom hexane.

Example 5 N-methyl-N (3-b romo-4-methoxybenzyl) urea may be prepared byreacting 3-bromo-4-methoxybenzylmethylamine with nitrourea. Afterrecrystallizing the product from 95 per cent alcohol it forms glossyleaflets, melting at about 178 C.

Example 6 CHzOlIr-N-C O-NH;

OCH:

N-methyl-N-(3-chloro-4-methoxyphenethyl) urea3-chloro-4-methoxyphenethylmethylamine is obtained by chlorination ofmethylhomoanisylamine, and is reacted with nitrourea. in aqueousalcohol, in the usual manner. The compound, recrystallized from ethylacetate, forms crystals melting about 118 0.

Example 7 C 2135-17-4] ONH:

N-etliyl-N- (3-bromo-6-ethoxypl1enyl) urea Acet-o-phenetidine isbrominated in acetic acid solution and the product, after purificationby recrystallization, is hydrolyzed by a mixture of alcohol andhydrochloric acid. The base, liberated from the hydrochloride, is thenN-ethylated by means of diethyl sulfate, and the resulting crudeethyl-3-bromo-6-ethoxyaniline purified via the nitroso compound in thecustomary manner. The amine so obtained is reacted with nitrourea inalcohol solution. After the reaction is over the alcohol is evaporated,water and salt are added and the mixture steam distilled. The residue,which solidifies on cooling, is recrystallized from suitable solvents,for example, ethyl acetate-hexane mixture, until pure, when it formswhite needles, melting at about 124 C.-125 C.

The foregoing examples are not to be taken as in any way delimiting theinvention, but are merely illustrative of the methods involved. Theinvention is to be limited only by the scope of the following cla ms.

What we claim is:

1. A substituted urea containing a single halogenated aromatic ring andno long chain groups, and represented by the formula in which Rrepresents an alkyl radical having from 2 to 4 carbon atoms; and Rrepresents a member of the group consisting of a halogenated phenylradical, a halogenated phenyl radical substituted on the nucleus atleast once by an alkyl radical of less than eight carbon atoms, and ahalogenated phenyl radical substituted on the nucleus at least once byan alkoxy radical of less than eight carbon atoms.

2. N-n-propyl-N- (4 bromo-2-methylphenyl) urea.

3. N-ethyl-N- (5 -chloro-2-methylphenyl) urea. 4. N-n-butyl-N-(4-bromo 2methylphenyl) urea.

JOI-IANNES S. BUCK. EDWIN J. DE BEER.

